Magnetic nanohydrogel obtained by miniemulsion polymerization of poly (acrylic acid) grafted onto derivatized dextran

This study describes the synthesis of magnetic nanohydrogels by miniemulsion polymerization technique. Dextran was derivatized by the glycidyl methacrylate to anchor vinyl groups on polysaccharides backbone, allowing its use as a macromonomer for miniemulsion polymerization, as confirmed by proton nuclear magnetic resonance spectroscopy (13C NMR).

Carbohydrate Polymers 178 (2017) 378–385 Contents lists available at ScienceDirect Carbohydrate Polymers journal homepage: www.elsevier.com/locate/carbpol Research Paper Magnetic nanohydrogel obtained by miniemulsion polymerization of poly (acrylic acid) grafted onto derivatized dextran MARK ⁎ Rodolfo Debone Piazzaa, , Eloiza da Silva Nunesb, Wesley Renato Vialib, Sebastião William da Silvac, Fermin Herrera Aragónc, José Antơnio Huamaní Coaquirac, Paulo César de Moraisd, Rodrigo Fernando Costa Marquesa, Miguel Jafelicci Júniora a Laboratory of Magnetic Materials and Colloids, Departament of Physical Chemistry, Institute of Chemistry, São Paulo State University, Araraquara, SP, 14801-970, Brazil b Instituto Federal Goiano, Rio Verde, GO 75901-970, Brazil c Instituto de Física, Núcleo de Física Aplicada, Universidade de Brasília, Brasília, DF, 70910-900, Brazil d Anhui University, School of Chemistry and Chemical Engineering, Hefei 230601, China A R T I C L E I N F O A B S T R A C T Keywords: Derivatized dextran Nanohydrogels Iron oxide Miniemulsion polymerization This study describes the synthesis of magnetic nanohydrogels by miniemulsion polymerization technique Dextran was derivatized by the glycidyl methacrylate to anchor vinyl groups on polysaccharides backbone, allowing its use as a macromonomer for miniemulsion polymerization, as confirmed by proton nuclear magnetic resonance spectroscopy (13C NMR) Magnetite nanoparticles were synthesized by coprecipitation, followed by air oxidation to maghemite The results of X-ray diffractometry (XRD), Raman and transmission electron microscopy (TEM) analysis showed that maghemite nanoparticles were obtained with a diameter of 5.27 nm The entrapment of iron oxide nanoparticles in a dextran nanohydrogel matrix was confirmed by thermogravimetric analysis (TGA), scanning transmission electron microscopy (STEM) and Zeta potential data The magnetic nanohydrogels presented superparamagnetic behavior and were colloidal stable in physiological during 30 days Our findings suggest that the synthesized magnetic nanohydrogel are potential candidates for use in drug delivery systems due to its physicochemical and magnetic properties Introduction In the last decade, the use of polymers nanoparticles (Biswas, Kumari, Lakhani, & Ghosh, 2015; Karami, Sadighian, Rostamizadeh, Parsa, & Rezaee, 2016; Lu & Park, 2013; Mandal et al., 2013; Masood, 2015; Ta, Convertine, Reyes, Stayton, & Porter, 2010) (Easo & Mohanan, 2013; Hervault & Thanh, 2014; Laurent et al., 2008; Pankhurst, Thanh, Jones, & Dobson, 2009) as platform for bioactive molecules have attracted attention due to their potential in targeting tumor tissues through passive delivery via enhanced permeability retention (EPR) effect (Bertrand, Wu, Xu, Kamaly, & Farokhzad, 2014) Polymer nanoparticles show high colloidal stability in addition to its versatility to retains bioactive molecules and delivery it when stimulated, increasing the biodistribution and avoiding premature drug delivery (Ganguly, Chaturvedi, More, Nadagouda, & Aminabhavi, 2014; Hoare & Kohane, 2008; Peppas, 1997) Polysaccharides show some advantages over synthetic polymers once they are abundant and obtained from renewable sources (Coviello, Matricardi, Marianecci, & Alhaique, 2007) Polysaccharides are ⁎ biocompatible, biodegradable, non-toxic and have free functional groups that can be used to modify their structure and/or anchor bioactive molecules, such as proteins, antibody and drugs (Dias, Hussain, Marcos, & Roque, 2011; Liu, Jiao, Wang, Zhou, & Zhang, 2008) Dextran is a suitable polysaccharide to prepare nanohydrogels and consists, predominantly, of α-1,6-glucosidic linkage, with some degree of branching in 1,3-linkage The dextran-based hydrogel is obtained by derivatization of its structure with vinyl groups, which can be polymerized with acrylic acid to control the crosslinking degree and pH-responsive behaviour (Medeiros, Santos, Fessi, & Elaissari, 2011) The use of nanohydrogels as drug carrier allows a greater drug load by the circulatory system, avoiding the chemical and enzymatic degradation before drug reach the targeted tissue (Ganguly et al., 2014; Iyer, Singh, Ganta, & Amiji, 2013; Liu et al., 2008; Wang et al., 2017) In addition to being capable to retain drug for a long circulation period, its desirable to guide the platform direct to the targeted site in the body, improving the therapy efficacy (Wassel, Grady, Kopke, & Dormer, 2007) To achieve this aim, nanohydrogels were supported onto Corresponding author E-mail addresses: rodolfo.piazza@iq.unesp.br, rodolfo.piazza@gmail.com (R.D Piazza) http://dx.doi.org/10.1016/j.carbpol.2017.09.019 Received 26 May 2017; Received in revised form 23 August 2017; Accepted September 2017 Available online 07 September 2017 0144-8617/ © 2017 Elsevier Ltd All rights reserved Carbohydrate Polymers 178 (2017) 378–385 R.D Piazza et al 2.3 Synthesis of SPION and functionalization with acrylic acid magnetic iron oxide nanoparticles, allowing it to be driven by an external magnetic field to specific site Iron oxide nanoparticles are also of great interest in biomedical applications such as hyperthermia, magnetic resonance imaging and drug delivery, due to their properties such as superparamagnetism, high surface to volume area, biocompatibility, and nontoxicity In order to avoid particle agglomeration towards physiological conditions during use in the afore mentioned applications, the surface of superparamagnetic iron oxide nanoparticles (SPION) should be functionalized with suitable molecules such as carboxylic acids (Lattuada & Hatton, 2007; Petri-Fink, Chastellain, Juillerat-Jeanneret, Ferrari, & Hofmann, 2005; Turcheniuk, Tarasevych, Kukhar, Boukherroub, & Szunerits, 2013), aminoacids (Durmus et al., 2011; Gholami, Rasoul-amini, Ebrahiminezhad, Seradj, & Ghasemi, 2015), and polymers, (e.g., dextran, chitosan, poly(ethylene glycol), etc.) (Arruebo et al., 2007; Durmus et al., 2011) The main contribution of this investigation was the magnetic nanohydrogels synthesis by miniemulsion polymerization This polymerization method shows particular features during the nucleation process, which results in nanoreactors formed by droplets with a limited volume of reaction (Luo, Dai, & Chiu, 2009; Mittal, 2011) The size of the resultant magnetic nanohydrogels should be comprised between 50 and 500 nm (Mittal, 2011), being suitable to passively targeting to the tumor cells (Bertrand et al., 2014) The maghemite nanoparticle was surface functionalized with acrylic acid for further encapsulation with a polymeric matrix composed of derivatized dextran and acrylic acid The magnetic nanohydrogels were obtained through vinyl polymerization with different amounts of functionalized iron oxide To the best of our knowledge, this is the first work describing the use of magnetic nanoparticles surface modified with derivatized dextran to be cross-linked in nanohydrogels using the miniemulsion polymerization instead of classical macroscopic hydrogels The synthesis of iron oxide nanoparticles was performed by coprecipitation of Fe2+ and Fe3+ A solution containing 0.04 mol of FeCl2·4H2O and 0.08 mol of FeCl3·6H2O dissolved in 500 mL of deionized water was added drop‐wise into 500 mL of 1.5 mol L−1 NaOH solution under mechanical stirring (2000 rpm) and constant bubbling on N2 gas at room temperature A black precipitate formed instantly and after 20 of reaction the solid was magnetically decanted and washed three times with deionized water The SPION were suspended in water and the pH was adjusted to 3.5 with 1.0 mol L−1 HCl solution The suspension was heated in a boiling water bath under constant magnetic stirring and air bubbling during h The reddish brown dispersion was dialyzed against water for days and stored for further use (Massart, 1981; Viali et al., 2010) The SPION concentration of 54.5 g L−1was obtained The surface functionalization of maghemite nanoparticles with acrylic acid was performed by adding 2.0 mL of 0.10 mol L−1 acrylic acid solution in 3.0 mL of SPION suspension, at pH 4.0 (Nunes, Lemos, & Carneiro, 2013) The acrylic acid adsorption was performed under continuous stirring for 48 h at room temperature and then the free acrylic acid was removed by dialysis The resulting dispersion was labeled as Magh-AA and used in further experiments 2.4 Synthesis of magnetic nanohydrogels The magnetic nanohydrogels were synthesized by inverse miniemulsion polymerization by using acrylic acid and derivatized dextran as monomers, in the ratio of 35% and 65% (w/w), respectively A Span®80 solution in n-heptane (4% (w/w), 40 mL) and a solution containing Magh-AA (different amounts of 50, 100, and 150 mg), AA (100.0 mg), Dex-GMA macromonomer (200.0 mg), NaOH (1.12 mmol), MBA (0.097 mmol) and APS (0.22 mmol) dissolved in 3.0 mL of deionized water was homogenized in a Turrax stirrer at 20000 rpm for and then submitted to an ultrasound probe for 30 min, an ice bath was used to avoid initiation of polymerization Afterward, 16 mg (0.15 mmol) of sodium bisulphite were added under ultra-sonication Sodium bisulphite and ammonium persulfate act as pair redox to decrease the temperature of thermodecomposition of initiators (Pohl & Rodriguez, 1981) The miniemulsion was transferred to a threeneck flask under magnetic stirring, purged for 15 with Argon flux, and then heated up to 50 °C for h After cooling to room temperature, the magnetic nanohydrogels were removed by centrifugation at 10000 rpm and washed thrice with hexane The particles were dispersed in a 0.5% Tween®80 aqueous solution and dialyzed against water for days Materials and methods 2.1 Materials All chemicals were used as received Iron(III) chloride hexahydrate (97%), Heptane (98.5%), and ammonium persulfate (APS) were purchased from Mallinckrodt Chemicals Dimethyl sulfoxide (DMSO, 99%) and 2-amino-2-hydroxymethyl-propane-1,3-diol (TRIS) were purchased from MERCK Sodium hydroxide (NaOH, 97%) was purchased from Synth Acrylic acid (AA, 97%) and 4-(dimethylamine) pyridine (DMAP, 99%) were purchased from Alfa Aesar Iron(II) chloride tetrahydrate (99%), dextran (MW 40 kDa), glycidyl methacrylate (GMA, 97%), N,N′methylenebisacrylamide (99%), sorbitan monooleate (Span®80), phosphate buffered saline (0.01 mol L−1 phosphate, 0.135 mol L−1 NaCl and 0.002 mol L−1 KCl) buffer solution (PBS) were purchased from Sigma-Aldrich Brazil 2.5 Samples characterization XRD powder diffraction of the samples was recorded in the 2θ range of 10–80° using the Siemens D5005 system equipped with a Cu Kα radiation source The XRD diffractograms were used to check the crystalline phase of the SPION-based material as well as to estimate the average crystallite size, the latter performed by using the Scherrer’s equation (Cullity, 1978) Raman scattering spectra were recorded at room temperature in a frequency range of 200–1000 cm−1 from a HORIBA Jobin Yvon model LabRAM HR micro Raman apparatus equipped with a 632.8 nm laser delivering 0.6 mW power The size and morphology of maghemite nanoparticles were investigated by transmission electron microscopy (TEM) Low magnification was obtained using a JEOL 3010 TEM-HR operating at 300 kV For TEM measurement, a drop of the sample dispersed in isopropanol was deposited on a copper grid covered with carbon film The morphology and size of nanohydrogels were investigated by transmission scanning electron microscopy (STEM) in a FEI Inspect F50 microscope For STEM analysis, the samples were dispersed in isopropanol and deposited in a 2.2 Dextran derivatization The dextran was modified through reaction with glycidyl methacrylate as described by van Dijk-Wolthuis et al (Hoof & Hennink, 1997; Steenbergenj, Bosch, & Hennint, 1995) The used molar ratio of dextran:GMA:DMAP was 1:0.5:0.25 with respect to 1.0 mol of glycosidic unit Dextran (1.5 g) and DMAP (2.4 mmol) were dissolved in 30.0 mL of DMSO in a three-neck round bottom flask under N2 atmosphere and magnetic stirring After complete dissolution, the system was heated up to 45 °C, then 4.8 mmol of GMA was injected into the flask, the temperature and stirring were kept for 24 h The reaction was stopped by adding an equimolar amount of HCl to neutralize DMAP The dextran modified polymer (Dex-GMA) was precipitate with acetone and dialyzed at °C The product was freeze-dried and a white powder was obtained 379 Carbohydrate Polymers 178 (2017) 378–385 R.D Piazza et al carbon coated copper grid The images were obtained in secondary electrons, bright field and high-angle annular dark field modes (HAADF) The FT-IR measurements were carried out using a Bruker VERTEX 70 FT-IR spectrometer equipped with a diffuse reflectance infrared Fourier transform (DRIFT) collector accessory, using the system resolution set at cm−1, while performing 256 scans 1H NMR spectroscopy was carried out on a Varian INOVA 300 spectrometer measuring samples dissolved in deuterium oxide Solid state 13C NMR measurements were carried out on Bruker Avance III HD 400WB spectrometer The powders were packed into mm rotors a spun at speeds of 10000 Hz, at fixed contact time of ms The deconvoluted spectral components were obtained using Voigt profile Thermogravimetric analyses (TGA) were carried out in STA 409C/CD system DTATGA from NETZSCH Instruments Samples (15 mg) were analyzed from room temperature up to 800 °C under 50 mL min−1 air flow, using a heating rate of 10 °C min−1 to estimate the net weight of the SPION in the magnetic nanohydrogel Hydrodynamic diameter and zeta potential of nanoparticle samples were measured using a Zetasizer Nanoseries ZSNano ZEN3600 from Malvern Instruments Hydrodynamic diameter was measured by dynamic light scattering (DLS), which samples were dispersed in water to size distribution, in NaCl mmol L−1 for pH dependence curve and in phosphate-buffered saline (PBS) or Tris buffer solution (pH 7.4) to colloidal stability measurments For zeta potential measurements the samples were previously dispersed in NaCl mmol L−1 solution Magnetization measurements were performed in powder form, using a commercial Physical Property Measurement System (PPMS) model 6000 platform with the vibrating sample magnetometer (VSM) module from Quantum Design Hysteresis loops (M‐H curves) were recorded in the range of −20 to 20 kOe, at temperatures of 300 K Zero-field-cooled (ZFC) and field-cooled (FC) curves were carried out in temperature range from −268 °C to 27 °C and applying a DC magnetic field of 30 Oe Results and discussion 3.1 Characterization of dextran macromonomer The polysaccharide dextran chains were modified by grafting methacrylate groups, through the reaction with GMA The DMAP act as a Lewis base and induces polarization of hydroxyl groups of dextran, allowing grafting of methacrylate groups in the polymer backbone (Lo & Jiang, 2010) The dextran derivatization can occur by two mechanisms: epoxy ring opening or transesterification, as show in Fig S1 on supplementary information In epoxy ring opening mechanism, the methylene carbon of the GMA undergoes a nucleophilic attack by hydroxyl groups of dextran, while the transesterification results in the attack at carbonyl ester of GMA DMSO, an aprotic polar solvent, was used in reaction environment to avoid reactions of GMA with water (Hoof & Hennink, 1997; Steenbergenj et al., 1995) Both mechanisms results in the methacrylate groups grafted to dextran chain The derivatization was evaluated by the 1H NMR spectroscopy (Fig 1A) and solid state 13C NMR spectroscopy (Fig 1B) From 1H NMR results, the signals between 3.10 ppm and 5.20 ppm corresponding to the dextran chain protons The anomeric proton of the glucopyranosyl ring has the signal shifted from the others protons at 4.91 ppm The peak at 5.20 ppm corresponds to α-1-4 linkage among dextran units The presence of methacrylate groups was confirmed for Dex_GMA sample The double doublet signals in 6.19 ppm and 5.70 ppm correspond to protons of vinyl group The single peak of methyl protons is observed at 1.90 ppm The degree of substitution (DS) of GMA on dextran can be calculated through 1H NMR spectrum, applying the equation DS = 100x/y, which x corresponds to the average integral of the vinyl doublets and y is the integral of anomeric proton plus 4% of α-1,4 linkages (Steenbergenj et al., 1995) The derivatization reaction presented a yield of 80.0% in mass of polymer and DS of 28.5% Derivatized dextran act as macromonomer, allowing further polymerization process Fig (A) 1H NMR spectra of dextran, glycidyl methacrylate (GMA) and dextran derivatized (B) Solid state 13C NMR spectra of dextran and dextran derivatized The 13C NMR spectra of dextran sample is show in Fig 1B The peak at 98.09 ppm correspond to anomeric carbon (C1), while the carbons (C2–C5) connected to hydroxyl groups show a signal at 72.15 ppm The carbon (C6) from eCH2 group of glycoside unit is assign to 65.46 ppm (Seymour, Knapp, & Bishop, 1976) The derivatized sample show additional peaks besides from pure dextran, which correspond to carbon atom from carbonyl group at 168.72 ppm The peaks at 136.28 and 128.26 are attributed to the carbons from vinyl groups, respectively, while the signal at 18.58 is due to CH2-Ch group Moreover, it is possible noted two peaks at 97.88 and 98.38 ppm on derivatized sample near to anomeric carbon instead of only one signal This shift indicated that the hydroxyl groups of C1 participated in the derivatization reaction (Zhang et al., 2014) The peak at 74–65 ppm was deconvoluted to Dex and Dex GMA samples, as can be seen in Fig S2, which result in shift of peaks positions, indicating that the derivatization reaction also occurs by the hydroxyls bound to these carbons 3.2 Characterization of SPION functionalized with acrylic acid The black precipitate of magnetite was obtained through the addition of sodium hydroxide to a solution of ferric and ferrous chloride, in a molar ratio of 2:1 The aqueous suspension of the magnetite was 380 Carbohydrate Polymers 178 (2017) 378–385 R.D Piazza et al directly oxidized by aeration to form a brownish suspension of maghemite XRD analysis (Fig S3(A)) of iron oxide sample Magh was indexed in the inverse spinel structure (Fd3m), in agreement with the protocols used to produce the superparamagnetic iron oxide SPION‐based materials The identification of structure of Magh sample was based on the Brag Peak Position of (1 1), (2 0), (3 1), (4 0), (4 2), (5 1) and (4 0) indices According to the International Centre for Diffraction Data (JCPDS Card N° 39-1346), the features exhibited by Magh sample can be assigned to the maghemite structure Broadening of the X-rays diffraction peaks is an indicative of the nanocrystalline nature of the synthesized powder (Cullity, 1978) The average X-rays crystallite diameter (DXRD) calculated by Scherrer’s equation was 6.2 nm and is in good agreement with electron microscopy data The Raman spectrum of SPION samples is shown in Fig S3(B) from 200 to 1000 cm−1 which vibrational modes are associated with maghemite crystal structure Typical Raman spectrum of maghemite is characterized by three main broad features, while magnetite shows only one feature broad structure, attributed to the A1g vibrational mode (Jubb & Allen, 2010) The Magh spectrum showed three bands at 345 cm−1 (Eg), 501 cm−1 (T2g), and 671 cm−1 (A1g) assigned to modes associated with tetrahedral iron sites, and one at 718 cm−1 assigned to the octahedral iron sites (Soler et al., 2011) Transmission electron microscopy was performed in order to access the Magh sample average particle size and morphology It can be observed in Fig 2(A) the TEM image of synthesized SPIONs with nearly spherical shape The Fig 2A inset shows particle size histogram of sample Magh obtained from the TEM micrographs This data was fitted to a log-normal distribution and results in average particle diameter (DTEM) of 5.27 ± 0.05 nm and polydispersity index (PDI) of 0.21 ± 0.01 The size distribution was also measurement by dynamic light scattering for Magh bare sample, which result in average hydrodynamic diameter of 48.50 ± 40 nm and PDI of 0.23 ± 0.01, as show in Fig 2(B) This value is higher than shown in TEM images due to electric double layer, which is involved during DLS measurement (Easo & Mohanan, 2013) The DRIFT analysis was used to confirm the functionalization of Magh nanoparticles by acrylic acid As show in Fig S4, the DRIFT spectrum illustrates the characteristics infrared absorption bands of Magh bare and Magh-AA The bands at 580 and 430 cm−1 correspond to FeeO stretching vibration modes The 3430 and 1600 cm−1 bands at the Magh bare can be assigned to eOeH stretching and bending vibrations, respectively, due to surface hydroxyl groups and water molecules adsorbed on the SPION surface (Cornell & Schwertmann, 2003; Nakamoto, 1970) The surface modification through acrylic acid addition was confirmed by the bands present at 1630 cm−1 assigned to carboxylate asymmetric and at 1434 cm−1 to symmetric stretching vibrations The weak band at 2911 cm−1 correspond to methine stretching of acrylic acid It was not possible to assign the C]C stretching of the vinyl group because it shows weak absorption at 1670–1640 cm−1, the same region for hydroxyl groups of SPION surface (Pavia, Lampman, & Kriz, 2001) Fig (A) TEM micrography of Magh bare sample The insert show particle size histogram, where vertical bars represent the experimental data whereas the solid line results from the curve fitting of the data using the log‐normal distribution function (B) Average hydrodynamic diameter distribution of Magh bare sample from DLS measurements It can be seen that size distribution of monomer droplet, before polymerization step, was comparable to polymer nanohydrogels sizes These results suggest that nanohydrogels are formed in a miniemulsion polymerization process According to FTIR spectra showed in Fig 3(A), the stretching vibrations of FeeO bond were observed in the same wavenumber of Magh bare sample Added to SPION absorptions bands, the characteristics of nanohydrogel correspond to the asymmetric and symmetric stretching at 2923 cm−1 and 2852 cm−1, respectively, that are assigned to CeH vibrations mode of dextran The bands at 1463 cm−1 and 1353 cm−1 were attributed to methylene and methyl bending absorptions The polysaccharides feature of CeOeC correspond to 1100 cm−1 stretching The band exhibited at 1739 cm−1 is attributed to carbonyl group of derivatized dextran and PAA (Pavia et al., 2001) Fig 3(B) shows the XRD pattern of magnetic nanohydrogels The presence of main diffraction peaks of magnetite, according to JCPDS Card N° 39-1346, confirm that any structural change occurs during polymerization step, excluding the formation of other types of iron oxides The width of diffraction peaks was broadened for magnetic nanohydrogels samples if compared with Magh bare sample in Fig S4(A) Fig shows the macroscopic and scanning transmission electron microscopy (STEM) images of the magnetic nanohydrogels Column (A) 3.3 Characterization of magnetic nanohydrogels The magnetic nanohydrogels were obtained through inverse miniemulsion polymerization In miniemulsion polymerization the droplet nucleation is the dominant mechanism of particle formation, which the monomer droplet being considered as a template for nanohydrogel formation, i.e the size of nanohydrogel should be similar to the initial monomer droplet size (Asua, 2002; Gyergyek, Makovec, Mertelj, Huskić, & Drofenik, 2010; Luo et al., 2009) The dynamic light scattering technique was used to evaluate the nanohydrogels size distribution The z-average sizes are summarized in Table S1 (size distribution profile is showed in Fig S5) The hydrodynamic diameter distribution of nanohydrogels is in the range between 100 and 400 nm 381 Carbohydrate Polymers 178 (2017) 378–385 R.D Piazza et al Table Summary of TGA data analysis on evaluation of SPION encapsulation SPION Magh‐bare Magh_Dex_50 Magh_Dex_100 Magh_Dex_150 Weight loss (%) Step I Step II 9.23 11.39 9.14 9.84 – 83,9 81,8 81,0 SPION residue (%) SPION/polymer 87.04 4.71 9.06 9.16 – 0.056 0.110 0.113 show the suspended magnetic nanohydrogels in water in the absence of magnetic field, while in column (B) the samples were attracted to the magnet The secondary electron image (column C) shows that the nanohydrogels particles have aggregated in a globules form These aggregates were formed during drying process of nanohydrogels suspension The encapsulation and distribution of iron oxide inside dextranbased nanohydrogels was evidenced by high-angle annular dark-field (HAADAF) and bright field images (Column D and E) The magnetic nanoparticles correspond to the black areas in the bright field image and to the bright areas in the HAADAF image The amount of SPION encapsulated by nanohydrogels was evaluated by TGA, in the range of 25–800 °C, as showed in Fig S6 The Magh-bare sample shows only one step of 9.23% weight loss assigned to adsorbed water up to 130 °C For magnetic nanohydrogels samples, two steps of weight loss were observed The first step was associated with adsorbed water weight loss, in agreement with the Magh-bare sample The second step, which starts at 165 °C and ends at 340 °C, was due to the decomposition of polymeric chains (Carp et al., 2009; Juríková, Csach, Koneracká, Kubov, & Kop, 2012) Table shows the weight loss attributed to each TGA event, the iron oxide residue and the mass ratio of SPION per polymer content The weight ratio among magnetic core content and nanohydrogels increased from 0.056 (sample Magh_Dex_50) to 0.113 (sample Magh_Dex_150) The results show that the sample Magh_Dex_100 reached the limit of encapsulation of SPION in dextran by inverse miniemulsion polymerization technique The magnetic properties of the samples were measured using magnetic hysteresis loop curves in the ± 20000 Oe window, at 27 °C, as showed in Fig 5(A) The saturation magnetization values were Fig (A) DRIFT spectra and (B) XRD patterns of magnetic nanohydrogel Fig Digital and STEM images of sample Magh_Dex_50 (upper) and Magh_Dex_150 (bottom): (A) Suspended magnetic nanohydrogel in absence of magnetic field, (B) in presence of magnetic field, (C) secondary electron image, (D) HAADAF and (E) bright field images 382 Carbohydrate Polymers 178 (2017) 378–385 R.D Piazza et al values of saturation magnetization, whether compared with our nanoparticles, mainly due to the size of SPION which influence the magnetic properties (Iida, Takayanagi, Nakanishi, & Osaka, 2007) However, the SPION content is increased using miniemulsion polymerization method, which result in increased the sample magnetization The superparamagnetic behavior is a desired magnetic property to use magnetic nanoparticle as drug delivery device On insert of Fig 5(A), it can be seen that samples show no coercivity and remanence values when the applied magnetic field was removed, suggesting that the nanoparticles showed superparamagnetic behaviour at 27.0 °C (Chou et al., 2012; Dou, Zhang, Jian, & Gu, 2010) To confirm that, zero field cooled (ZFC) and field cooled (FC) curves were obtained for all samples, as shown in Fig 5(B) As observed, all samples show features consistent with a superpamagnetic behavior; i e., a maximum in the ZFC trace and irreversible behavior between both traces below that maximum Moreover, the position of the maximum (Tm) shows a dependence with the amount of coating For the Magh bare sample the maximum is located at −178 °C and that maximum is shifted to lower temperature for the magnetic nanohydrogel samples This result strongly suggests that the particle–particle magnetic interactions are relatively stronger for the bare sample and those interactions become weaker as the amount of coating is increased 3.4 Colloidal stability Nanohydrogels were evaluated through zeta potential measurements in pH-dependence curve The Magh-bare and magnetic nanohydrogels samples were measured in the constant ionic strength of mmol L−1 NaCl, as showed in Fig (upper) The amphoteric features of SPION are due to ionization of surface hydroxyl groups Thus, the adsorption or desorption of protons have a pH dependence In acid medium, the surface is protonated and the zeta potential value is positive On the other hand, the zeta potential is negative when the surface is deprotonated in basic solution The isoelectric point (IEP) for Magh-bare was 8.2, which is in accordance with literature reports (Cornell & Schwertmann, 2003; Hajdú et al.,2012) The IEP for Magh AA sample was shift to 6.0 The magnetic nanohydrogels samples Fig (A) Magnetization versus applied field curves for Magh bare nanoparticles and magnetic nanohydrogels The experimental data were normalized with respect to the iron oxide mass The insert shows hysteresis loops near zero (B) Zero-field-cooled (ZFC) and field-cooled (FC) curves as function of the temperature obtained with a DC magnetic field of H = 30 Oe normalized to the mass of iron oxide using TGA data (Medford et al., 2014) According to literature, the values of saturation magnetization for maghemite bulk were 83.5 emu g−1 (Cullity and Graham, 2009), while the Magh-bare sample this value decreased to 28.9 emu g−1 Decrease in saturation magnetization values of SPION with respect to the saturation magnetization of bulk counterparts is often observed in nanoparticles and is attributed to the surface contribution of spin canting, surface disorder, stoichiometric deviation, cation distribution (Kodama, 1999) and adsorbed layer species (Zhang, Su, Wen, & Li, 2008) For Magh_Dex_50, Magh_Dex_100 and Magh_Dex_150 samples the values of saturation magnetization were 32.6 emu g−1, 23.9 emu g−1 and 28.9 emu g−1, respectively Magnetic nanohydrogel based on P(NIPPAm-co-AAc) synthesized by (Chou, Shih, Tsai, Chiu, & Lue, 2012) and (Fan, Li, Wu, Li, & Wu, 2011) showed different Fig pH dependence of zeta potential (upper) and pH dependence of hydrodynamic diameter (bottom) for Magh bare, Magh AA nanoparticles and magnetic nanohydrogels 383 Carbohydrate Polymers 178 (2017) 378–385 R.D Piazza et al nanoparticles with desirable superparamagnetic behavior for biomedical applications were encapsulated by dextran nanohydrogels The samples Magh_Dex_50 and Magh_Dex_100 resulted in stable dispersion in buffer solutions at physiological pH indicating its colloidal stability The synergy between iron oxide nanoparticles and dextran nanohydrogel make this composite a good candidate for drug delivery systems Table Magnetic nanohydrogels average hydrodynamic diameter/polydispersivity index (PDI) measured in different buffers Sample Magh_Dex50 Magh_Dex100 Magh_Dex150 PBS (pH 7.4) Tris.HCl (pH 7.4) Dh (nm)/PDI t = days Dh (nm)/PDI t = 30 days Dh (nm)/PDI t = days Dh (nm)/PDI t = 30 days 259.2/0.230 237.0/0.381 527.3/0.295 273.6/0.220 246.9/0.121 218.5/0.205 212.0/0.256 241.0/0.199 611.5/0.428 234.5/0.244 160.9/0.204 248.9/0.424 Acknowledgements The authors thank the financial support of the Brazilian agencies São Paulo State Research Foundation (FAPESP), Coordination for Higher Education Personnel Improvement (CAPES), Brazilian Innovation Agency (FINEP) and National Council of Technological and Scientific Development (CNPq) We would like to thank Electron Microscopy Laboratory of Brazilian Nanotechnology National Laboratory LME/LNNano/CNPEM for electron microscopy investigation facilities and technical support Magh_Dex_50, Magh_Dex_100, and Magh_Dex_150 not reach the IEP along of the pH range studied and show minimum zeta potential values at pH 2.0 of −0.16 mV, −0.47 mV and −1.04 mV, respectively This behavior can be attributed to the carboxylic acid groups arising from the acrylic acid moieties present in the polymeric matrix and the sulfate groups from APS shear layer (Eissa et al., 2013) The zeta potential values were constants for magnetic nanohydrogels samples above pH 6.5 Fig (bottom) shows the hydrodynamic diameter in the pH range from 2.0 to 10.0, measured at a constant ionic strength of mmol L-1 NaCl The hydrodynamic diameter of Magh bare sample increase above pH 5.0 Although the potential zeta value indicate stability at this pH, no electrostatic or steric repulsion were predicted to this sample Moreover, attractive dipolar magnetic force act in this sample, hindering the aggregates dispersion, until the instrument reached the limit of measurement (5 μm) To Magh AA sample, an increase in hydrodynamic diameter was observed on isoelectric region, however, due to steric stabilization promoted by acrylic acid, the aggregation is not strong and the hydrodynamic diameter is restored The magnetic nanohydrogels samples show an increase in the average size near pH 3.0, which causes particle coagulation due to decrease in the electrostatic repulsion between nanohydrogels caused by protonation of the carboxylate groups from the polymeric chains, as indicated in zeta potential curve (Fig upper) In fact, the magnetic nanohydrogels exhibit good colloidal stability and was observed no variation in hydrodynamic diameter over a range of pH between 6.5–10.0 where the zeta potential reaches constant values above −25.0 mV In this pH range, the electrostatic repulsion is maximized due to complete deprotonation of the carboxylate groups The colloidal stability of the magnetic nanohydrogels was evaluated in buffer solution of tris.HCl and PBS, in pH 7.4 The hydrodynamic diameters were measured during a 30 days period, as showed in Table The magnetic nanohydrogels were stabilized by steric repulsion promoted by the polymeric chains composed of dextran and the polyacrylate moieties Thus, the magnetic nanohydrogels were stable over 30 days, once the hydrodynamic diameters did not show any significant increase over this period, except the sample Magh_Dex_150, in which the hydrodynamic diameter has increased to above 500 nm for both buffers solutions after the sample dispersion This result may be related to the formation of aggregates after dispersion in buffer solution After a period of days, the aggregates sedimented and hydrodynamic diameter of the remained dispersed nanoparticles reach a steady state to 248.9 nm for tris.HCl and 218.5 nm for PBS Appendix A Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.carbpol.2017.09.019 References Arruebo, M., Fernández-Pacheco, R., Velasco, B., Marquina, C., Arbiol, J., Irusta, S., Santamaría, J (2007) Antibody-functionalized hybrid superparamagnetic nanoparticles Advanced Functional Materials, 17(9), 1473–1479 http://dx.doi.org/10 1002/adfm.200600560 Asua, J M (2002) Miniemulsion polymerization Progress in Polymer Science, 27(7), 1283–1346 http://dx.doi.org/10.1016/s0079-6700(02)00010-2 Bertrand, N., Wu, J., Xu, X., Kamaly, N., & Farokhzad, O C (2014) Cancer nanotechnology: The impact of 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